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Abstract Neuroepithelial tumors with fusion of PLAGL1 or amplification of PLAGL1/PLAGL2 have recently been described often with ependymoma-like or embryonal histology respectively. To further evaluate emerging entities with PLAG-family genetic alterations, the histologic, molecular, clinical, and imaging features are described for 8 clinical cases encountered at St. Jude (EWSR1-PLAGL1 fusion n = 6; PLAGL1 amplification n = 1; PLAGL2 amplification n = 1). A histologic feature observed on initial resection in a subset (4/6) of supratentorial neuroepithelial tumors with EWSR1-PLAGL1 rearrangement was the presence of concurrent ependymal and ganglionic differentiation. This ranged from prominent clusters of ganglion cells within ependymoma/subependymoma-like areas, to interspersed ganglion cells of low to moderate frequency among otherwise ependymal-like histology, or focal areas with a ganglion cell component. When present, the combination of ependymal-like and ganglionic features within a supratentorial neuroepithelial tumor may raise consideration for an EWSR1-PLAGL1 fusion, and prompt initiation of appropriate molecular testing such as RNA sequencing and methylation profiling. One of the EWSR1-PLAGL1 fusion cases showed subclonal INI1 loss in a region containing small clusters of rhabdoid/embryonal cells, and developed a prominent ganglion cell component on recurrence. As such, EWSR1-PLAGL1 neuroepithelial tumors are a tumor type in which acquired inactivation of SMARCB1 and development of AT/RT features may occur and lead to clinical progression. In contrast, the PLAGL2 and PLAGL1 amplified cases showed either embryonal histology or contained an embryonal component with a significant degree of desmin staining, which could also serve to raise consideration for a PLAG entity when present. Continued compilation of associated clinical data and histopathologic findings will be critical for understanding emerging entities with PLAG-family genetic alterations.

Abstract In recent years computational methods for molecular modeling have become a prime focus of computational biology and cheminformatics. Many dedicated systems exist for modeling specific classes of molecules such as proteins or small drug-like ligands. These are often heavily tailored toward the automated generation of molecular structures based on some meta-input by the user and are not intended for expert-driven structure assembly. Dedicated manual or semi-automated assembly software tools exist for a variety of molecule classes but are limited in the scope of structures they can produce. In this work we present BuildAMol, a highly flexible and extendable, general-purpose fragment-based molecular assembly toolkit. Written in Python and featuring a well-documented, user-friendly API, BuildAMol empowers researchers with a framework for detailed manual or semi-automated construction of diverse molecular models. Unlike specialized software, BuildAMol caters to a broad range of applications. We demonstrate its versatility across various use cases, encompassing generating metal complexes or the modeling of dendrimers or integrated into a drug discovery pipeline. By providing a robust foundation for expert-driven model building, BuildAMol holds promise as a valuable tool for the continuous integration and advancement of powerful deep learning techniques. Scientific contribution BuildAMol introduces a cutting-edge framework for molecular modeling that seamlessly blends versatility with user-friendly accessibility. This innovative toolkit integrates modeling, modification, optimization, and visualization functions within a unified API, and facilitates collaboration with other cheminformatics libraries. BuildAMol, with its shallow learning curve, serves as a versatile tool for various molecular applications while also laying the groundwork for the development of specialized software tools, contributing to the progress of molecular research and innovation.

Abstract Background The Dual-Active Ingredient long-lasting insecticidal nets (Dual-AI LLIN) have been developed to counteract the reduced efficacy of pyrethroid (PY)-only nets due to widespread pyrethroid insecticide resistance in malaria vector mosquitoes. They constitute half of the nets distributed in sub-Saharan Africa between 2022 and 2024. However, their effectiveness once they develop holes is unclear, particularly in pyrethroid-resistant settings. This study evaluates the textile integrity of three dual- AI LLINs compared to standard PY LLN, over 3 years of use in a community in Tanzania and the associated impact on malaria prevalence and incidence. Methods A secondary analysis of data from a randomized controlled trial (RCT) in North-western Tanzania was conducted to evaluate the effectiveness of α-cypermethrin only; pyriproxyfen and α-cypermethrin (PPF-PY); chlorfenapyr and α-cypermethrin (chlorfenapyr-PY); and the synergist piperonyl butoxide and permethrin (PBO-PY) LLINs on malaria infection prevalence and case incidence. The association between the net textile condition and 1/malaria prevalence over 3 years of use between 2019 and 2022, and 2/malaria case incidence in a cohort of children over 2 years of follow-up was assessed between 2019 and 2021. Results There was no significant association between damaged (OR 0.98, 95% CI 0.71–1.37, p-value = 0.655) and too-torn (OR 1.07, 95% CI 0.77–1.47, p-value = 0.694) compared to intact nets on malaria prevalence for all net types. However, there were reduced rates of malaria case incidence in children sleeping under a net in good condition compared to too-torn nets (incidence rate ratio (IRR) 0.76 [95% CI 0.63–0.92], p = 0.005). Malaria incidence was also consistently lower in too-torn PBO-PY LLIN (IRR = 0.37 [95% CI 0.19–0.72], p = 0.003) and chlorfenapyr-PY LLIN (IRR = 0.45 [95% CI 0.33–0.97], p = 0.053) compared to an intact PY-only LLIN during the first year of follow up. In year 2, the incidence was only significantly lower in intact chlorfenapyr-PY LLIN (IRR = 0.49 [95% CI 0.29–0.81], p = 0.006) compared to intact PY LLIN. Conclusion The study confirmed that sleeping under a chlorfenapyr-PY LLIN or PBO-PY LLIN offered superior protection to pyrethroid-only nets even when torn. Preventing the development of holes is essential as they impact the level of protection offered against malaria infection. Trial registration: ClinicalTrials.gov, number (NCT03554616)

Objectives: This study assesses exposure to malaria vector mosquitos that is nonpreventable through use of nets, the contribution of outdoor and indoor biting towards residual vector exposure, and the risk factors for being bitten and for being infected with malaria parasites on Bioko Island, Equatorial Guinea. Methods: Human behavior and malaria infection data were collected from 13,735 randomly selected residents during cross-sectional surveys, concomitantly with entomological human landing catches, indoors and outdoors, in 20 locations on the Island. Self-reported time of going indoors, going to bed and whether using a net were analyzed to impute for each respondent the number of bites received outdoors and indoors during the night before the survey. Results: On average, each person received 2.7 (95% CI: 2.6-2.8) bites per night outdoors, 8.5 (8.3 to 8.7) bites indoors if not using a net, and 4.7 (4.5 to 4.8) bites indoors if using a net. Malaria infection was associated with more bites, regardless of whether received indoors or outdoors. Older age, male gender, not using a net, rural location, and going indoors later increased the risk of being bitten. The proportion of bites not averted by using a net was estimated as 66% (61 to 71). Conclusions: A large proportion of biting, mostly indoors, may not be preventable by bednets. Tools targeting indoor biting should be prioritized in Bioko. Novel vector control tools are urgently needed to reduce overall exposure to mosquito bites.

For the computation of vibrationally resolved electronic spectra, various approaches can be employed. Adiabatic approaches simulate vibronic transitions using harmonic potentials of the initial and final states, while vertical approaches extrapolate the final state potential from the gradients and Hessian at the Franck–Condon point, avoiding a full exploration of the potential energy surface of the final state. Our implementation of the vertical Hessian (VH) method has been validated with a benchmark set of four small molecules, each presenting unique challenges, such as complex topologies, problematic low-frequency vibrations, or significant geometrical changes upon electronic excitation. We assess the quality of both adiabatic and vertical approaches for simulating vibronic transitions. For two types of donor–acceptor compounds with promising thermally activated delayed fluorescence properties, our computations confirm that the vertical approaches outperform the adiabatic ones. The VH method significantly reduces computational costs and yields meaningful emission spectra, where adiabatic models fail. More importantly, we pioneer the use of the VH method for the computation of rate constants for non-radiative processes, such as intersystem crossing and reverse intersystem crossing along a relaxed interpolated pathway of a donor–acceptor compound. This study highlights the potential of the VH method to advance computational vibronic spectroscopy by providing meaningful simulations of intricate decay pathway mechanisms in complex molecular systems. [ABSTRACT FROM AUTHOR]

Since emergence of the highly pathogenic avian influenza virus (HPAIV) H5 A/Goose/Guangdong/1/1996 (gs/GD) lineage in 1996, successors continue to circulate in waves around the world, leading to massive losses in [...]

Abstract Background Malaria elimination requires closely co-ordinated action between neighbouring countries. In Southern Africa several countries have reduced malaria to low levels, but the goal of elimination has eluded them thus far. The Southern Africa Development Community (SADC) Malaria Elimination Eight (E8) initiative was established in 2009 between Angola, Botswana, Eswatini, Mozambique, Namibia, South Africa, Zambia, and Zimbabwe to coordinate malaria interventions aiming to eliminate malaria by 2030. Cross-border coordination is important in malaria elimination settings as it strengthens surveillance, joint planning and implementation, knowledge exchange and optimal use of resources. This paper describes how this collaboration is realized in practice, its achievements and challenges, and its significance for malaria elimination prospects. Methods The ministers of health of the E8 countries oversee an intergovernmental technical committee supported by specialist working groups consisting of technical personnel from member countries and partner institutions. These technical working groups are responsible for malaria elimination initiatives in key focus areas such as surveillance, vector control, diagnosis, case management, behaviour change and applied research. The technical working groups have initiated and guided several collaborative projects which lay essential groundwork for malaria elimination. Results The E8 collaboration has yielded achievements in the following key areas. (1) Establishment and evaluation of malaria border health posts to improve malaria services in border areas and reduce malaria among resident and, mobile and migrant populations. (2) The development of a regional malaria microscopy slide bank providing materials for diagnostic training and proficiency testing. (3) A facility for regional external competency assessment and training of malaria microscopy trainers in collaboration with the World Health Organization. (4) Entomology fellowships that improved capacity in entomological surveillance; an indoor residual spraying (IRS) training of trainers’ scheme to enhance the quality of this core intervention in the region. (5) Capacity development for regional malaria parasite genomic surveillance. (6) A mechanism for early detection of malaria outbreak through near real time reporting and a quarterly bulletins of malaria incidence in border districts. Conclusions The E8 technical working groups system embodies inter-country collaboration of malaria control and elimination activities. It facilitates sustained interaction between countries through a regional approach. The groundwork for elimination has been laid, but the challenge will be to maintain funding for collaboration at this level whilst reducing reliance on international donors and to build capacities necessary to prepare for malaria elimination.

Per- and polyfluoroalkyl substances (PFAS) are a broad class of synthetic chemicals; some are present in most humans in developed countries. Some studies suggest that certain PFAS may have immunotoxic effects in humans, which could put individuals with high levels of exposure at increased risk for infectious diseases such as COVID-19. We conducted a case-control study to examine the association between COVID-19 diagnosis and PFAS serum concentrations among employees and retirees from two 3 M facilities, one of which historically generated perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS). Participants completed enrollment and follow-up study visits in the Spring of 2021. Participants were categorized as cases if they reported a COVID-19 diagnosis or became sick with at least one symptom of COVID-19 when someone else in their household was diagnosed, otherwise they were categorized as a control. COVID-19 diagnosis was modeled in relation to concentration of serum PFAS measured at enrollment after adjusting for covariates. The analytic sample comprised 573 individuals, 111 cases (19.4%) and 462 controls (80.6%). In adjusted models, the odds ratio of COVID-19 was 0.94 per interquartile range (14.3 ng/mL) increase in PFOS (95% confidence interval 0.85, 1.04). Results for PFOA, PFHxS, and perfluorononanoic acid (PFNA) were similar. Other PFAS present at lower concentrations were examined as categorical variables (above the limit of quantification [LOQ], yes vs. no [referent category]), and also showed no positive associations. In our study, which used individual-level data and included people with high occupational exposure, the serum concentrations of all PFAS examined were not associated with an increased odds ratio for COVID-19. At this point, the epidemiologic data supporting no association of COVID-19 occurrence with PFAS exposure are stronger than those suggesting a positive association.

Abstract Catheter-associated urinary tract infections (CAUTIs), a common cause of healthcare-associated infections, are caused by a diverse array of pathogens that are increasingly becoming antibiotic resistant. We analyze the microbial occurrences in catheter and urine samples from 55 human long-term catheterized patients collected over one year. Although most of these patients were prescribed antibiotics over several collection periods, their catheter samples remain colonized by one or more bacterial species. Examination of a total of 366 catheter and urine samples identify 13 positive and 13 negative genus co-occurrences over 12 collection periods, representing associations that occur more or less frequently than expected by chance. We find that for many patients, the microbial species composition between collection periods is similar. In a subset of patients, we find that the most frequently sampled bacteria, Escherichia coli and Enterococcus faecalis, co-localize on catheter samples. Further, co-culture of paired isolates recovered from the same patients reveals that E. coli significantly augments E. faecalis growth in an artificial urine medium, where E. faecalis monoculture grows poorly. These findings suggest novel strategies to collapse polymicrobial CAUTI in long-term catheterized patients by targeting mechanisms that promote positive co-associations.

Abstract We consider non-Lorentzian expansions, Galilean and Carrollian, of the Lorentz force equation in which both the particle position and the electro-magnetic field are expanded. There are two well-known limits in the case of a constant field, called electric and magnetic, that are studied separately. We show that the resulting equations of motion follow equivalently from considering a non-linear realisation of a certain infinite-dimensional algebras.

Abstract We develop in detail the general framework of consistent Kaluza-Klein truncations from D=11 and type II supergravities to gauged maximal supergravities in two dimensions. In particular, we unveil the complete bosonic dynamics of all gauged maximal supergravities that admit a geometric uplift. Our construction relies on generalised Scherk-Schwarz reductions of E9 exceptional field theory. The application to the reduction of D=11 supergravity on S 8 × S 1 to SO(9) gauged supergravity is presented in a companion paper.

Abstract Eleven-dimensional supergravity on S 8 × S 1 is conjectured to be dual to the M-theory matrix model. We prove that the dynamics of a subset of fluctuations around this background is consistently described by D = 2 SO(9) gauged maximal supergravity. We provide the full non-linear uplift formulæ for all bosonic fields. We also present a further truncation to the SO(3)×SO(6) invariant sector and discuss its relation to the BMN matrix model at finite temperature. The construction relies on the framework of generalised Scherk-Schwarz reductions, established for E9 exceptional field theory in a companion paper. As a by-product, we severely constrain the most general gauge deformations in D = 2 admitting an uplift to higher dimensions.

Abstract Background Medication prescribing and discontinuation processes are complex and involve the patient, numerous health care professionals, organizations, health information technology (IT). CancelRx is a health IT that automatically communicates medication discontinuations from the clinic electronic health record to the community pharmacy dispensing platform, theoretically improving communication. CancelRx was implemented across a Midwest academic health system in October 2017. The health system also operates 15 outpatient community pharmacies. Objective The goal of this qualitative study was to describe how both the clinic and community pharmacy work systems change and interact over time regarding medication discontinuations, before and after CancelRx implantation. Approach Medical Assistants (n = 9), Community Pharmacists (n = 12), and Pharmacy Administrators (n = 3), employed by the health system were interviewed across 3-time periods between 2017 and 2018— 3-months prior to CancelRx implementation, 3-months after CancelRx implementation, and 9-months after CancelRx implementation. Interviews were audio recorded, transcribed, and conducted a hybrid analysis with deductive content analysis following the Systems Engineering Initiative for Patient Safety (SEIPS) framework and inductive analysis to capture additional codes and themes. Key results CancelRx changed the medication discontinuation process at both clinics and community pharmacies. In the clinics, the workflows and medication discontinuation tasks changed over time while MA roles and clinic staff communication practices remained variable. In the pharmacy, CancelRx automated and streamlined how medication discontinuation messages were received and processed, but also increased workload for the pharmacists and introduced new errors. Conclusions This study utilizes a systems approach to assess disparate systems within a patient network. Future studies may consider health IT implications for systems that are not in the same health system as well as assessing the role of implementation decisions on health IT use and dissemination.

In a 1-year survey of wild terrestrial predators in northern Germany, we found that 5 of 110 foxes were infected with contemporary avian influenza A(H5N1) viruses, forming a temporal cluster during January‒March 2023. Encephalitis and strong cerebral virus replication but only sporadic mammalian-adaptive viral polymerase basic 2 protein E627K mutations were seen.

Abstract This manuscript is a master statistical analysis plan for each of three-cluster randomized controlled trials to evaluate the efficacy of attractive targeted sugar baits (ATSB) described in an already published protocol. The master SAP contains an overarching plan for all three trials, which can be adapted to trial-specific circumstances. The primary objective of the trials is to evaluate the efficacy of ATSB in the presence of universal vector control coverage with insecticide-treated nets (ITN) or indoor residual spraying (IRS) after two transmission seasons on clinical malaria incidence as compared with universal vector control coverage with ITN or IRS alone. The primary outcome measure is the incidence rate of clinical malaria, assessed in cohorts aged 12 months to less than 15 years (≥ 5 years to 15 years in Mali) during monthly follow-up visits. The primary unadjusted analysis will be conducted on the intention-to-treat analysis population without adjustment for any anticipated confounding variables. The primary outcome will be analyzed using a multi-level model constructed on a generalized linear model framework with a Poisson likelihood and a log link function. Random intercepts will be included for each study cluster and a fixed effect for study-arm. The analyst will be blinded to study arm assignment. Several secondary outcomes will be analyzed, as well as a pooled analysis (individual patient data meta-analysis) across the three trial sites. Additionally, a standard meta-analysis is expected to be conducted using combined data from all sites.

The aim of this work was to demonstrate the potential of the concept of clean-label-capable flow additives. These are spray-dried food ingredients whose particle size is small enough (

BackgroundParticularly in rural regions, factors such as lower physician density and long travel distances complicate adequate outpatient care. However, urban regions can also be affected by deficits in care, for example, long waiting times. One model of care intending to improve the situation is the implementation of video consultations. The study protocol presents the methodology of the research project titled “Preference-based implementation of the video consultation in urban and rural regions” funded by the German Federal Joint Committee (funding number 01VSF20011). ObjectiveThis study aims to identify existing barriers to the use of video consultation and the preferences of insured individuals and physicians as well as psychotherapists in order to optimize its design and thus increase acceptance and use of video consultations in urban and rural regions. MethodsBuilt on a mixed methods approach, this study first assesses the status quo of video consultation use through claims data analysis and carries out a systematic literature review on barriers and promoting factors for the use of video consultations. Based on this preliminary work, focus groups are conducted in order to prepare surveys with insureds as well as physicians and psychotherapists in the second study phase. The central element of the survey is the implementation of discrete choice experiments to elicit relevant preferences of (potential) user groups and service providers. The summarized findings are discussed in a stakeholder workshop and translated into health policy recommendations. ResultsThe methodological approach used in this study is the focus of this paper. The study is still ongoing and will continue until March 2024. The first study phase has already been completed, in which preliminary work has been done on potential applications and hurdles for the use of video consultations. Currently, the survey is being conducted and analyses are being prepared. ConclusionsThis study is intended to develop a targeted strategy for health policy makers based on actual preferences and perceived obstacles to the use of video consultations. The results of this study will contribute to further user-oriented development of the implementation of video consultations in German statutory health insurance. Furthermore, the iterative and mixed methods approach used in this study protocol is also suitable for a variety of other research projects. International Registered Report Identifier (IRRID)DERR1-10.2196/50932

Abstract Background The importation of parasites across borders remains a threat to malaria elimination. The Southern African Development Community Malaria Elimination Eight (E8) established 39 border health facilities on 5 key international borders between high and low-burden countries. These clinics aimed to improve access to prevention, diagnosis, and treatment of malaria for residents in border areas and for mobile and migrant populations who frequently cross borders. Studies were conducted in each of the four high-burden E8 countries (Angola, Mozambique, Zambia, and Zimbabwe) to evaluate malaria services in border areas. Methods Cross-sectional surveys were conducted within 30 km of recently established E8 Border Health Posts. Structured questionnaires were administered to randomly selected respondents to assess malaria-related knowledge and behavior, access to malaria prevention, diagnosis and treatment of malaria, and risk factors for malaria associated with local and cross-border travel. Results Results showed that most providers followed appropriate guidelines performing blood tests when individuals presented with fever, and that nearly all those who reported a positive blood test received medication. Lack of access to health care due to distance, cost or mistrust of the provider was rare. A minority of respondents reported not receiving timely diagnosis either because they did not seek help, or because they were not offered a blood test when presenting with fever. There was a high level of correct knowledge of causes, symptoms, and prevention of malaria. A majority, of border residents had access to primary prevention against malaria through either long-lasting insecticidal nets (LLINs) or indoor residual spraying (IRS). Cross border travel was common with travellers reporting sleeping outside without protection against malaria. Conclusions The study demonstrated the importance of border health facilities in providing access to malaria services. Prevention needs to be improved for people who travel and sleep outdoors. Community health workers can play a key role in providing access to information, testing and treating malaria.